Exhibit 10.1

KARYOPHARM THERAPEUTICS INC.

January 23, 2015

Michael Kauffman, M.D., Ph.D.

c/o Karyopharm Therapeutics Inc.

85 Wells Avenue

Newton, MA 02459

Dear Michael:

Subject to your execution below, this letter hereby amends the employment letter, dated December 6, 2010, between you and Karyopharm Therapeutics Inc. (the “Company ” ) and provides for the following terms of employment:

1. Position . You will continue to serve as Chief Executive Officer, reporting to the Company’s Board of Directors (the “ Board ”). In your role you will have the responsibilities customarily associated with such position and those that are assigned to you by the Company’s Board. During the term of your employment with the Company, you will devote your full professional time and efforts to the business of the Company, except that you may engage in other activities that may be approved in advance by the Company’s Board of Directors (the “ Board ” ). You will continue to be a member of the Board.

2. Compensation .

a. Base Salary . Effective January 1, 2015, you will be paid an annual base salary of Five Hundred Thousand Dollars ($500,000). Your base salary will be payable pursuant to the Company’s regular payroll policy. Your salary will be reviewed annually and may be increased by the Board in connection with any such review.

b. Bonus Program . Effective January 1, 2015, you will be eligible for an annual bonus that targets sixty percent (60%) of your annual base salary based upon achievement of certain performance goals and corporate milestones established by the Board in consultation with you. Achievement of goals will be determined in the sole discretion of the Board or a Compensation Committee of the Board. To earn any part of the bonus, you must be employed on December 31st of the applicable bonus year and such bonus shall be paid no later than March 15th of the year immediately following the year to which the applicable annual bonus relates. Your bonus target will be reviewed annually and may be modified by the Board in connection with any such review.

c. Option Grants . You are eligible for annual option grants in the Company’s sole discretion.

d. Withholding . The Company shall withhold from any compensation or benefits payable under this letter agreement any federal, state and local income, employment or other similar taxes as may be required to be withheld pursuant to any applicable law or regulation.

3. Benefits .

a. Vacation and Holidays . You will be eligible for four weeks of paid vacation each year and Company paid holidays consistent with the Company’s vacation policy offered to other executive level employees of the Company.

b. Other . You will be eligible to participate in such medical, retirement and other benefits as are approved by the Board and made available to other executive level employees of the Company.

As is the case with all employee benefits, such benefits will be governed by the terms and conditions of applicable plans or policies, which are subject to change or discontinuation at any time.

4. At-Will Employment . Your employment with the Company is and shall at all times during your employment hereunder be “at-will” employment. The Company or you may terminate your employment at any time for any reason, with or without Cause, as defined in Section 5(d), and with or without notice. The “at-will” nature of your employment shall remain unchanged during your tenure as an employee of the Company, and may only be changed by an express written agreement that is signed by you and the Board.

5. Termination of Employment

a. If you resign your employment with the Company or if the Company terminates your employment other than for “Cause” you will receive: (i) any unpaid base salary for services rendered prior to the date of termination or resignation; (ii) any earned but unpaid annual bonus for any year prior to the year in which termination of employment occurs; (iii) reimbursement of any un-reimbursed business expenses incurred as of the date of termination or resignation in accordance with the Company’s reimbursement policy, (iv) accrued but unused vacation (if applicable), earned through the effective resignation or termination date; and (v) all other payments, benefits or fringe benefits to which you shall be entitled under the terms of any applicable compensation arrangement or benefit, equity or fringe benefit plan or program or grant or this letter agreement (collectively, clauses (i) through (v) shall be referred herein as the “Accrued Benefits ” ), and, except as set forth in paragraph (b), you will not be entitled to any other compensation except as the Board may otherwise agree in its sole discretion. If the Company terminates your employment for Cause, at any time, then you will receive no additional compensation other than the Accrued Benefits, except that the benefits described in Section 5(a)(ii) shall not be paid to you.

b. If the Company terminates your employment other than for “Cause” or if you terminate your employment for “Good Reason”, as such terms are defined below, subject to you providing the Company with a fully effective separation agreement that includes a general release of claims in a form and manner reasonably satisfactory to the Company (the “Release ” ) within the 30-day period following the date of termination, the Company shall, in addition to the amounts payable under paragraph (a), (i) in the case of the termination of your employment by the Company other than for “Cause” or by you for “Good Reason”, in either case, prior to a Change of Control, (x) pay you severance pay in the form of continuation of your base salary for twelve (12) months (the “Non-COC Severance Period ” ) and (y) provided you elect to continue your and your eligible dependents’ participation in the Company’s medical and dental benefit plans pursuant to the Consolidated Omnibus Budget Reconciliation Act of

2

1986 (“COBRA”), pay the monthly premium to continue such coverage for the lesser of the twelve (12) full calendar months immediately following the month in which the termination of your employment occurs and the end of the calendar month in which you become eligible to receive group health plan coverage under another employee benefit plan or (ii) in the case of the termination of your employment by the Company other than for “Cause” or by you for “Good Reason”, in either case, after a Change of Control, (x) pay you severance pay in the form of continuation of your base salary for eighteen (18) months (the “COC Severance Period ” ) in accordance with the Company’s payroll practice, beginning on the Company’s first regular payroll date that occurs 30 days after the date of termination and (y) provided you elect to continue your and your eligible dependents’ participation in the Company’s medical and dental benefit plans pursuant to COBRA, pay the monthly premium to continue such coverage for the lesser of the eighteen (18) full calendar months immediately following the month in which the termination of your employment occurs and the end of the calendar month in which you become eligible to receive group health plan coverage under another employee benefit plan (as applicable, the “Severance Benefits” ). Solely for purposes of Section 409A of the Internal Revenue Code of 1986, as amended (the “Code ” ), each salary continuation payment is considered a separate payment. To the extent that any Severance Benefit constitutes “non-qualified deferred compensation” under Section 409A of the Code, then such payments or benefits shall be payable only upon the Executive’s “separation from service.” The determination of whether and when a separation from service has occurred shall be made in accordance with the presumptions set forth in Treasury Regulation Section 1.409A-l(h). Notwithstanding the foregoing, the Severance Benefits will be reduced dollar for dollar by any compensation you receive from another employer during the period between the date of termination of your employment and the end of the Non-COC Severance Period or COC Severance Period, as applicable, if you become re-employed during such period. You agree to give prompt written notice of any employment during the Non-COC Severance Period or COC Severance Period, as applicable, and to respond promptly to any reasonable inquiries concerning your professional activities. If the Company makes any overpayment of Severance Benefits, you agree to promptly return any such overpayment to the Company. The foregoing shall not create any obligation on your part to seek reemployment after the date of termination of your employment.

For purposes of this paragraph, the following terms will have the following meanings:

(i) “Good Reason ” shall mean that you have complied with the “Good Reason Process,” as defined below, following the occurrence of any of the following events after a Change of Control: (i) a material diminution in your responsibilities, authority or duties; (ii) you are not elected to, or are removed, from the surviving company’s Board; (iii) you are made to report to anyone other than the surviving company’s Board; or (iv) the surviving company’s corporate headquarters are located outside Massachusetts.

(ii) “Good Reason Process ” shall mean that (i) you reasonably determine in good faith that a “Good Reason” condition has occurred; (ii) you notify the Company in writing of the first occurrence of the Good Reason condition within ten (10) days of the first occurrence of such condition; (iii) you cooperate in good faith with the Company’s efforts, for a period not less than thirty (30) days following such notice (the “Cure Period ” ), to remedy the condition; (iv) notwithstanding such efforts, the Good Reason condition continues to exist; and (v) you terminate your employment within thirty (30) days after the end of the Cure Period. If the Company cures the Good Reason condition during the Cure Period, Good Reason shall be deemed not to have occurred.

3

(iii) “Change of Control ” shall mean any of the following:

1. any “person,” as such term is used in Sections 13(d) and 14(d) of the Securities Exchange Act of 1934, as amended (the “Act”) (other than the Company, any of its subsidiaries, or any trustee, fiduciary or other person or entity holding securities under any employee benefit plan or trust of the Company or any of its subsidiaries), together with all “affiliates” and “associates” (as such terms are defined in Rule 12b-2 under the Act) of such person, shall become the “beneficial owner” (as such term is defined in Rule 13d-3 under the Act), directly or indirectly, of securities of the Company representing fifty percent (50%) or more of the combined voting power of the Company’s then outstanding securities having the right to vote in an election of the Board (“Voting Securities”) in such case other than as a result of an acquisition of securities directly from the Company; or

2. the date a majority of the members of the Board is replaced during any 12-month period by directors whose appointment or election is not endorsed by a majority of the members of the incumbent Board before the date of the appointment or election, provided, further that directors whose initial assumption of office is in connection with an actual or threatened election contest related to the election of directors of the Company will not be considered as members of the incumbent Board for purposes of this paragraph for a period of twelve (12) months following such initial assumption; or

3. the consummation of (A) any consolidation or merger of the Company where the stockholders of the Company, immediately prior to the consolidation or merger, would not, immediately after the consolidation or merger, beneficially own (as such term is defined in Rule 13d-3 under the Act), directly or indirectly, shares representing in the aggregate more than fifty percent (50%) of the voting shares of the Company issuing cash or securities in the consolidation or merger (or of its ultimate parent corporation, if any,), or (B) any sale or other transfer (in one transaction or a series of transactions contemplated or arranged by any party as a single plan) of all or substantially all of the assets of the Company.

Notwithstanding the foregoing, a “Change in Control” shall not be deemed to have occurred for purposes of the foregoing clause (i) solely as the result of an acquisition of securities by the Company which, by reducing the number of shares of Voting Securities outstanding, increases the proportionate number of Voting Securities beneficially owned by any person to fifty percent (50%) or more of the combined voting power of all of the then outstanding Voting Securities; provided, however, that if any person referred to in this sentence shall thereafter become the beneficial owner of any additional shares of Voting Securities (other than pursuant to a stock split, stock dividend, or similar transaction or as a result of an acquisition of securities directly from the Company) and immediately thereafter beneficially owns fifty percent (50%) or more of the combined voting power of all of the then outstanding Voting Securities, then a “Change in Control” shall be deemed to have occurred for purposes of this letter agreement.

4

c. If your employment terminates because of your death or Disability, then you will receive the Accrued Benefits. For purposes of this letter agreement, “Disability” shall be defined as your inability to have performed your material duties hereunder due to a physical or mental injury, infirmity or incapacity for one hundred eighty (180) days (including weekends and holidays) in any 365-day period.

For purposes of this letter agreement, “for Cause” shall mean: (i) dishonesty, embezzlement, misappropriation of assets or property of the Company; (ii) gross negligence, willful misconduct, neglect of duties, theft, fraud or breach of fiduciary duty to the Company; (iii) violation of federal or state securities law; (iv) the conviction of a felony or any crime involving moral turpitude, including a plea of guilty or nolo contendre ; (v) a material breach of any of the Company’s written policies related to conduct or ethics; or (vi) a material breach of the Nondisclosure and Inventions Assignment Agreement, dated January 1, 2011, between you and the Company (the “Confidentiality Agreement ” ).

6. Employee Confidentiality Agreement . As an employee of the Company, you will have access to certain Company and third party confidential information and you may during the course of your employment develop certain information or inventions which will be the property of the Company. You acknowledge the continuing effectiveness of the Confidentiality Agreement.

7. Resolution of Disputes . Any controversy or claim arising out of or relating to your employment, this letter agreement, its enforcement or interpretation, or because of an alleged breach, default, or misrepresentation in connection with any of its provisions, shall be submitted to arbitration in Boston, Massachusetts before a single arbitrator (applying Massachusetts law), in accordance with the National Rules for the Resolution of Employment Disputes then in effect of the American Arbitration Association ( “ AAA ” ) as modified by the terms and conditions of this Section 7; provided , however , that provisional injunctive relief may, but need not, be sought in a court of law while arbitration proceedings are pending, and any provisional injunctive relief granted by such court shall remain effective until the matter is finally determined by the arbitrator. The arbitrator shall be selected by mutual agreement of the parties or, if the parties cannot agree, by striking from a list of arbitrators supplied by AAA. The arbitrator shall issue a written opinion revealing, however briefly, the essential findings and conclusions upon which the award is based. Final resolution of any dispute through arbitration may include any remedy or relief which the arbitrator deems just and equitable. Any award or relief granted by the arbitrator hereunder shall be final and binding on the parties hereto and may be enforced by any court of competent jurisdiction.

The parties acknowledge that they are hereby waiving any rights to trial by jury in any action, proceeding or counterclaim brought by either of the parties against the other in connection with any matter whatsoever arising out of or in any way connected with this letter agreement or your employment.

The Company shall pay the arbitrator’s fees and arbitration expenses and any other costs associated with the arbitration or arbitration hearing that are unique to arbitration. The Company and you each shall separately pay its or your own deposition, witness, expert and attorneys’ fees and other expenses as and to the same extent as if the matter were being held in court unless otherwise provided by law. The arbitrator shall have the sole and exclusive power and authority to decide any and all issues of or related to whether this letter agreement or any provision of this letter agreement is subject to arbitration.

5

8. No Inconsistent Obligations . By accepting this offer of employment, you represent and warrant to the Company that you are under no obligations or commitments, whether contractual or otherwise, that are inconsistent with your obligations set forth in this letter agreement or that would be violated by your employment by the Company. You agree that you will not take any action on behalf of the Company or cause the Company to take any action that will violate any agreement that you have with a prior employer.

9. Indemnification and Liability Insurance . The Company will provide you certain rights to indemnification as set forth in the Company’s standard form of indemnification agreement for executive officers and directors.

10. Miscellaneous .

a. This letter agreement may be executed in several counterparts, each of which shall be deemed to be an original but all of which together will constitute one and the same instrument.

b. The Company may only assign this letter agreement to a successor (whether direct or indirect, by purchase, merger, consolidation or otherwise) to all or substantially all of the business and/or assets of the Company, provided , that such successor expressly agrees to assume and perform this letter agreement in the same manner and to the same extent that the Company would have been required to perform it if no such assignment had taken place, and “Company” shall include any such successor that assumes and agrees to perform this letter agreement, by operation of law or otherwise.

c. No provision of this letter agreement may be modified, waived or discharged unless such waiver, modification or discharge is agreed to in writing and signed by you and such officer or director as may be designated by the Board. No waiver by either party hereto at any time of any breach by the other party hereto of, or compliance with, any condition or provision of this letter agreement to be performed by such other party shall be deemed a waiver of similar or dissimilar provisions or conditions at the same or at any prior or subsequent time.

11. The validity, interpretation, construction and performance of this letter agreement shall be governed by the laws of the Commonwealth of Massachusetts without regard to the choice of law principles thereof.

If you have any further questions or require additional information, please feel free to contact me.

[Signatures appear on following page]

6

7

Exhibit 10.2

KARYOPHARM THERAPEUTICS INC.

January 23, 2015

Sharon Shacham, Ph.D., M.B.A.

c/o Karyopharm Therapeutics Inc.

85 Wells Avenue

Newton, MA 02459

Dear Sharon:

Subject to your execution below, this letter hereby amends the employment letter, dated October 19, 2010, as amended on December 6, 2010, between you and Karyopharm Therapeutics Inc. (the “Company” ) and provides for the following terms of employment:

1. Position . You will continue to serve as President and Chief Scientific Officer, reporting to the Company’s Chief Executive Officer. In your role you will have the responsibilities customarily associated with such position and those that are assigned to you by the Company’s Chief Executive Officer. During the term of your employment with the Company, you will devote your full professional time and efforts to the business of the Company, except that you may engage in other activities that may be approved in advance by the Company’s Board of Directors (the “ Board ” ).

2. Compensation .

a. Base Salary . Effective January 1, 2015, you will be paid an annual base salary of Four Hundred Twelve Thousand Dollars ($412,000). Your base salary will be payable pursuant to the Company’s regular payroll policy. Your salary will be reviewed annually and may be increased by the Board in connection with any such review.

b. Bonus Program . Effective January 1, 2015, you will be eligible for an annual bonus that targets fifty percent (50%) of your annual base salary based upon achievement of certain performance goals and corporate milestones established by the Board in consultation with you. Achievement of goals will be determined in the sole discretion of the Board or a Compensation Committee of the Board. To earn any part of the bonus, you must be employed on December 31st of the applicable bonus year and such bonus shall be paid no later than March 15th of the year immediately following the year to which the applicable annual bonus relates. Your bonus target will be reviewed annually and may be modified by the Board in connection with any such review.

c. Option Grants . You are eligible for annual option grants in the Company’s sole discretion.

d. Withholding . The Company shall withhold from any compensation or benefits payable under this letter agreement any federal, state and local income, employment or other similar taxes as may be required to be withheld pursuant to any applicable law or regulation.

3. Benefits .

a. Vacation and Holidays . You will be eligible for four weeks of paid vacation each year and Company paid holidays consistent with the Company’s vacation policy offered to other executive level employees of the Company.

b. Other . You will be eligible to participate in such medical, retirement and other benefits as are approved by the Board and made available to other executive level employees of the Company.

As is the case with all employee benefits, such benefits will be governed by the terms and conditions of applicable plans or policies, which are subject to change or discontinuation at any time.

4. At-Will Employment . Your employment with the Company is and shall at all times during your employment hereunder be “at-will” employment. The Company or you may terminate your employment at any time for any reason, with or without Cause, as defined in Section 5(d), and with or without notice. The “at-will” nature of your employment shall remain unchanged during your tenure as an employee of the Company, and may only be changed by an express written agreement that is signed by you and the Board.

5. Termination of Employment

a. If you resign your employment with the Company or if the Company terminates your employment other than for “Cause” you will receive: (i) any unpaid base salary for services rendered prior to the date of termination or resignation; (ii) any earned but unpaid annual bonus for any year prior to the year in which termination of employment occurs; (iii) reimbursement of any un-reimbursed business expenses incurred as of the date of termination or resignation in accordance with the Company’s reimbursement policy, (iv) accrued but unused vacation (if applicable), earned through the effective resignation or termination date; and (v) all other payments, benefits or fringe benefits to which you shall be entitled under the terms of any applicable compensation arrangement or benefit, equity or fringe benefit plan or program or grant or this letter agreement (collectively, clauses (i) through (v) shall be referred herein as the “Accrued Benefits” ), and, except as set forth in paragraph (b), you will not be entitled to any other compensation except as the Board may otherwise agree in its sole discretion. If the Company terminates your employment for Cause, at any time, then you will receive no additional compensation other than the Accrued Benefits, except that the benefits described in Section 5(a)(ii) shall not be paid to you.

b. If the Company terminates your employment other than for “Cause” or if you terminate your employment for “Good Reason”, as such terms are defined below, subject to you providing the Company with a fully effective separation agreement that includes a general release of claims in a form and manner reasonably satisfactory to the Company (the “Release ” ) within the 30-day period following the date of termination, the Company shall, in addition to the amounts payable under paragraph (a), (i) in the case of the termination of your employment by the Company other than for “Cause” or by you for “Good Reason”, in either case, prior to a Change of Control, (x) pay you severance pay in the form of continuation of your base salary for nine (9) months (the “Non-COC Severance Period ” ) and (y) provided you elect to continue your and your eligible dependents’ participation in the Company’s medical and dental benefit plans pursuant to the Consolidated Omnibus Budget Reconciliation Act of

2

1986 (“COBRA”), pay the monthly premium to continue such coverage for the lesser of the nine (9) full calendar months immediately following the month in which the termination of your employment occurs and the end of the calendar month in which you become eligible to receive group health plan coverage under another employee benefit plan or (ii) in the case of the termination of your employment by the Company other than for “Cause” or by you for “Good Reason”, in either case, after a Change of Control, (x) pay you severance pay in the form of continuation of your base salary for twelve (12) months (the “COC Severance Period ” ) in accordance with the Company’s payroll practice, beginning on the Company’s first regular payroll date that occurs 30 days after the date of termination and (y) provided you elect to continue your and your eligible dependents’ participation in the Company’s medical and dental benefit plans pursuant to COBRA, pay the monthly premium to continue such coverage for the lesser of the twelve (12) full calendar months immediately following the month in which the termination of your employment occurs and the end of the calendar month in which you become eligible to receive group health plan coverage under another employee benefit plan (as applicable, the “Severance Benefits ” ). Solely for purposes of Section 409A of the Internal Revenue Code of 1986, as amended (the “Code ” ), each salary continuation payment is considered a separate payment. To the extent that any Severance Benefit constitutes “non-qualified deferred compensation” under Section 409A of the Code, then such payments or benefits shall be payable only upon the Executive’s “separation from service.” The determination of whether and when a separation from service has occurred shall be made in accordance with the presumptions set forth in Treasury Regulation Section 1.409A-l (h). Notwithstanding the foregoing, the Severance Benefits will be reduced dollar for dollar by any compensation you receive from another employer during the period between the date of termination of your employment and the end of the Non-COC Severance Period or COC Severance Period, as applicable, if you become re-employed during such period. You agree to give prompt written notice of any employment during the Non-COC Severance Period or COC Severance Period, as applicable, and to respond promptly to any reasonable inquiries concerning your professional activities. If the Company makes any overpayment of Severance Benefits, you agree to promptly return any such overpayment to the Company. The foregoing shall not create any obligation on your part to seek reemployment after the date of termination of your employment.

For purposes of this paragraph, the following terms will have the following meanings:

(i) “Good Reason ” shall mean that you have complied with the “Good Reason Process,” as defined below, following the occurrence of any of the following events after a Change of Control: (i) a material diminution in your responsibilities, authority or duties; (ii) you are made to report to anyone other than the surviving company’s Board or Chief Executive Officer; or (iii) the surviving company’s corporate headquarters are located outside Massachusetts.

(ii) “Good Reason Process ” shall mean that (i) you reasonably determine in good faith that a “Good Reason” condition has occurred; (ii) you notify the Company in writing of the first occurrence of the Good Reason condition within ten (10) days of the first occurrence of such condition; (iii) you cooperate in good faith with the Company’s efforts, for a period not less than thirty (30) days following such notice (the “Cure Period ” ), to remedy the condition; (iv) notwithstanding such efforts, the Good Reason condition continues to exist; and (v) you terminate your employment within thirty (30) days after the end of the Cure Period. If the Company cures the Good Reason condition during the Cure Period, Good Reason shall be deemed not to have occurred.

3

(iii) “Change of Control ” shall mean any of the following:

1. any “person,” as such term is used in Sections 13(d) and 14(d) of the Securities Exchange Act of 1934, as amended (the “Act”) (other than the Company, any of its subsidiaries, or any trustee, fiduciary or other person or entity holding securities under any employee benefit plan or trust of the Company or any of its subsidiaries), together with all “affiliates” and “associates” (as such terms are defined in Rule 12b-2 under the Act) of such person, shall become the “beneficial owner” (as such term is defined in Rule 13d-3 under the Act), directly or indirectly, of securities of the Company representing fifty percent (50%) or more of the combined voting power of the Company’s then outstanding securities having the right to vote in an election of the Board (“Voting Securities”) in such case other than as a result of an acquisition of securities directly from the Company; or

2. the date a majority of the members of the Board is replaced during any 12-month period by directors whose appointment or election is not endorsed by a majority of the members of the incumbent Board before the date of the appointment or election, provided, further that directors whose initial assumption of office is in connection with an actual or threatened election contest related to the election of directors of the Company will not be considered as members of the incumbent Board for purposes of this paragraph for a period of twelve (12) months following such initial assumption; or

3. the consummation of (A) any consolidation or merger of the Company where the stockholders of the Company, immediately prior to the consolidation or merger, would not, immediately after the consolidation or merger, beneficially own (as such term is defined in Rule 13d-3 under the Act), directly or indirectly, shares representing in the aggregate more than fifty percent (50%) of the voting shares of the Company issuing cash or securities in the consolidation or merger (or of its ultimate parent corporation, if any,), or (B) any sale or other transfer (in one transaction or a series of transactions contemplated or arranged by any party as a single plan) of all or substantially all of the assets of the Company.

Notwithstanding the foregoing, a “Change in Control” shall not be deemed to have occurred for purposes of the foregoing clause (i) solely as the result of an acquisition of securities by the Company which, by reducing the number of shares of Voting Securities outstanding, increases the proportionate number of Voting Securities beneficially owned by any person to fifty percent (50%) or more of the combined voting power of all of the then outstanding Voting Securities; provided, however, that if any person referred to in this sentence shall thereafter become the beneficial owner of any additional shares of Voting Securities (other than pursuant to a stock split, stock dividend, or similar transaction or as a result of an acquisition of securities directly from the Company) and immediately thereafter beneficially owns fifty percent (50%) or more of the combined voting power of all of the then outstanding Voting Securities, then a “Change in Control” shall be deemed to have occurred for purposes of this letter agreement.

c. If your employment terminates because of your death or Disability, then you will receive the Accrued Benefits. For purposes of this letter agreement, “Disability” shall be defined as your

4

inability to have performed your material duties hereunder due to a physical or mental injury, infirmity or incapacity for one hundred eighty (180) days (including weekends and holidays) in any 365-day period. Notwithstanding the foregoing, in the event that as a result of earlier absence because of mental or physical incapacity you incur a “separation from service” within the meaning of such term under Code Section 409A you shall on such date automatically be terminated from employment as a Disability termination.

For purposes of this letter agreement, “for Cause” shall mean: (i) dishonesty, embezzlement, misappropriation of assets or property of the Company; (ii) gross negligence, willful misconduct, neglect of duties, theft, fraud or breach of fiduciary duty to the Company; (iii) violation of federal or state securities law; (iv) the conviction of a felony or any crime involving moral turpitude, including a plea of guilty or nolo contendre ; (v) a material breach of any of the Company’s written policies related to conduct or ethics; or (vi) a material breach of the Nondisclosure and Inventions Assignment Agreement, dated October 22, 2010, between you and the Company (the “Confidentiality Agreement ” ).

6. Employee Confidentiality Agreement . As an employee of the Company, you will have access to certain Company and third party confidential information and you may during the course of your employment develop certain information or inventions which will be the property of the Company. You acknowledge the continuing effectiveness of the Confidentiality Agreement.

7. Resolution of Disputes . Any controversy or claim arising out of or relating to your employment, this letter agreement, its enforcement or interpretation, or because of an alleged breach, default, or misrepresentation in connection with any of its provisions, shall be submitted to arbitration in Boston, Massachusetts before a single arbitrator (applying Massachusetts law), in accordance with the National Rules for the Resolution of Employment Disputes then in effect of the American Arbitration Association ( “ AAA ” ) as modified by the terms and conditions of this Section 7; provided , however , that provisional injunctive relief may, but need not, be sought in a court of law while arbitration proceedings are pending, and any provisional injunctive relief granted by such court shall remain effective until the matter is finally determined by the arbitrator. The arbitrator shall be selected by mutual agreement of the parties or, if the parties cannot agree, by striking from a list of arbitrators supplied by AAA. The arbitrator shall issue a written opinion revealing, however briefly, the essential findings and conclusions upon which the award is based. Final resolution of any dispute through arbitration may include any remedy or relief which the arbitrator deems just and equitable. Any award or relief granted by the arbitrator hereunder shall be final and binding on the parties hereto and may be enforced by any court of competent jurisdiction.

The parties acknowledge that they are hereby waiving any rights to trial by jury in any action, proceeding or counterclaim brought by either of the parties against the other in connection with any matter whatsoever arising out of or in any way connected with this letter agreement or your employment.

The Company shall pay the arbitrator’s fees and arbitration expenses and any other costs associated with the arbitration or arbitration hearing that are unique to arbitration. The Company and you each shall separately pay its or your own deposition, witness, expert and attorneys’ fees and other expenses as and to the same extent as if the matter were being held in court unless otherwise provided by law. The arbitrator shall have the sole and exclusive power and authority to decide any and all issues of or related to whether this letter agreement or any provision of this letter agreement is subject to arbitration.

5

8. No Inconsistent Obligations . By accepting this offer of employment, you represent and warrant to the Company that you are under no obligations or commitments, whether contractual or otherwise, that are inconsistent with your obligations set forth in this letter agreement or that would be violated by your employment by the Company. You agree that you will not take any action on behalf of the Company or cause the Company to take any action that will violate any agreement that you have with a prior employer.

9. Indemnification and Liability Insurance . The Company will provide you certain rights to indemnification as set forth in the Company’s standard form of indemnification agreement for executive officers and directors.

10. Miscellaneous .

a. This letter agreement may be executed in several counterparts, each of which shall be deemed to be an original but all of which together will constitute one and the same instrument.

b. The Company may only assign this letter agreement to a successor (whether direct or indirect, by purchase, merger, consolidation or otherwise) to all or substantially all of the business and/or assets of the Company, provided , that such successor expressly agrees to assume and perform this letter agreement in the same manner and to the same extent that the Company would have been required to perform it if no such assignment had taken place, and “Company” shall include any such successor that assumes and agrees to perform this letter agreement, by operation of law or otherwise.

c. No provision of this letter agreement may be modified, waived or discharged unless such waiver, modification or discharge is agreed to in writing and signed by you and such officer or director as may be designated by the Board. No waiver by either party hereto at any time of any breach by the other party hereto of, or compliance with, any condition or provision of this letter agreement to be performed by such other party shall be deemed a waiver of similar or dissimilar provisions or conditions at the same or at any prior or subsequent time.

11 . The validity, interpretation, construction and performance of this letter agreement shall be governed by the laws of the Commonwealth of Massachusetts without regard to the choice of law principles thereof.

If you have any further questions or require additional information, please feel free to contact me.

[Signatures appear on following page]

6

7

Exhibit 10.3

KARYOPHARM THERAPEUTICS INC.

January 23, 2015

Justin Renz

c/o Karyopharm Therapeutics Inc.

85 Wells Avenue

Newton, MA 02459

Dear Justin:

Subject to your execution below, this letter hereby amends the employment letter, dated July 2, 2014, between you and Karyopharm Therapeutics Inc. (the “Company” ) and provides for the following terms of employment:

The terms of your position with the Company are as set forth below:

1. Position . You will continue to serve as Executive Vice President, Chief Financial Officer, and Treasurer, reporting to the Company’s Chief Executive Officer. In your role you will have the responsibilities customarily associated with such position and those that are assigned to you by the Company’s Chief Executive Officer. During the term of your employment with the Company, you will devote your full professional time and efforts to the business of the Company, except that you may engage in other activities that may be approved in advance by the Company’s Board of Directors (the “Board” ).

2. Compensation .

a. Base Salary. Effective January 1, 2015, you will be paid an annualized base salary of Three Hundred Fifty-Five Thousand Dollars ($355,000), subject to tax and other withholdings required by law. Your base salary will be payable pursuant to the Company’s regular payroll policy. Your salary may be adjusted from time to time in accordance with normal business practices and in the sole discretion of the Company.

b. Bonus Program. Effective January 1, 2015, you will be eligible for an annual bonus that targets forty percent (40%) of your annualized base salary based upon achievement of certain performance goals and corporate milestones established by the Company. Achievement of goals will be determined in the sole discretion of the Board of Directors of the Company (the “Board”) or a Compensation Committee of the Board. To earn any part of the bonus, you must be employed on December 31 ^st of the applicable bonus year. Your bonus target may be adjusted from time to time in accordance with normal business practices and in the sole discretion of the Company.

c. Option Grants . You are eligible for annual option grants in the Company’s sole discretion.

d. Severance Compensation. If the Company (which, for the purposes of this paragraph, includes any successor entity) terminates the term of your employment without Cause, or you resign for Good Reason, the Company will continue to pay you your base compensation at its then-current rate, in accordance with the Company’s then-current regular payroll procedures for employees, for at least six (6) months (subject to upward adjustment in the event that standardized severance terms are authorized for all employees of your level and such terms exceed the severance amount provided herein) following the date

of such termination, provided that you execute a release of any and all claims that you may have against the Company arising from your employment with the Company, reasonably satisfactory to the Company in form and substance. Additionally, provided you elect to continue your and your eligible dependents’ participation in the Company’s medical and dental benefit plans pursuant to the Consolidated Omnibus Budget Reconciliation Act of 1986 (“COBRA”), the Company will pay the monthly premium to continue such coverage for the lesser of the six (6) full calendar months immediately following the month in which the termination of your employment occurs and the end of the calendar month in which you become eligible to receive group health plan coverage under another employee benefit plan. Notwithstanding the foregoing, if your employment is terminated without Cause, or you resign for Good Reason, within one year following the consummation of a Change in Control (as defined below), then the Company (or its successor entity) will continue to pay you your base compensation at its then-current rate, in accordance with the Company’s (or successor’s) then-current regular payroll procedures for employees, for at least twelve (12) months following the date of such termination, provided that you execute a release of any and all claims that you may have against the Company (or its successor) arising from your employment with the Company and/or its successor, reasonably satisfactory to the Company or its successor in form and substance. Additionally, provided you elect to continue your and your eligible dependents’ participation in the Company’s medical and dental benefit plans pursuant to COBRA, the Company will pay the monthly premium to continue such coverage for the lesser of the twelve (12) full calendar months immediately following the month in which the termination of your employment occurs and the end of the calendar month in which you become eligible to receive group health plan coverage under another employee benefit plan. For purposes of this Offer Letter, “Change in Control” shall mean the sale of all or substantially all of the outstanding shares of capital stock, assets or business of the Company, by merger, consolidation, sale of assets or otherwise (other than a transaction in which all or substantially all of the individuals and entities who were beneficial owners of the capital stock of the Company immediately prior to such transaction beneficially own, directly or indirectly, more than 50% of the outstanding securities (on an as-converted to Common Stock basis) entitled to vote generally in the election of directors of the (i) resulting, surviving or acquiring corporation in such transaction in the case of a merger, consolidation or sale of outstanding shares, or (ii) acquiring corporation in the case of a sale of assets.

“Cause” shall mean (i) an act or acts of material willful misconduct by you in violation of law or government regulation in the course of your employment by the Company, (ii) your conviction by a court of competent jurisdiction of theft or misappropriation by you of assets of the Company, (iii) your conviction by a court of competent jurisdiction of fraud committed by you or at your direction, (iv) your conviction by a court of competent jurisdiction of, or pleading “guilty” or “no contest” to, (x) a felony or (y) any other criminal charge that has, or could be reasonably expected to have, a material adverse impact on the Company or the performance of your duties, (v) willful, repeated and material failure to perform, or gross negligence in the performance of, the duties which are reasonably assigned to you by the Company, (vi) material breach of any agreement to which you and the Company are party and/or (vii) failure to fully participate in a Company investigation as may be reasonably requested by the Company; provided, however, that you shall have a period of thirty (30) days to cure (if curable) any act constituting Cause under clauses (v) or (vii) of this paragraph, following the Company’s delivery to you of written notice, setting forth in reasonable detail the facts and circumstances claimed to provide a basis for the termination for Cause.

“Good Reason” shall mean (i) the assignment to you of any duties inconsistent in any adverse, material respect with your position, authority, duties or responsibilities as then constituted, or any other action by the Company which results in a material diminution in such position, authority, duties or

responsibilities, (ii) a reduction in the aggregate of your base or incentive compensation by greater than ten percent (10%) or the termination of your rights to any employee benefits, except to the extent that any such benefit is replaced with a comparable benefit, or a reduction in scope or value thereof, other than as a result of across-the-board reductions or terminations affecting employees of the Company generally, or (iii) a requirement that you, without your prior consent, regularly report to work at a location that is thirty (30) miles or more away from your then current place of work; provided , however , that the conditions described immediately above in clauses (i) through (iii) shall not give rise to a termination for Good Reason, unless you have notified the Company in writing within thirty (30) days of the first occurrence of the facts and circumstances claimed to provide a basis for the termination for Good Reason, the Company has failed to correct the condition within fifteen (15) days after the Company’s receipt of such written notice, and you actually terminate employment with the Company within forty-five (45) days of the first occurrence of the condition. For the avoidance of doubt, your required travel on the Company’s business shall not be deemed a relocation of your principal office under clause (iii), above.

e. Withholding . The Company shall withhold from any compensation or benefits payable under this letter agreement any federal, state and local income, employment or other similar taxes as may be required to be withheld pursuant to any applicable law or regulation.

4. Benefits .

a. Vacation and Holidays . You will be eligible for a maximum of 20 days of paid vacation each year and Company paid holidays consistent with the Company’s vacation policy (including accrual of vacation days).

b. Other . You will be eligible to participate in such medical, retirement and other benefits as are approved by the Board and made available to other employees of the Company.

As is the case with all employee benefits, such benefits will be governed by the terms and conditions of applicable plans or policies, which are subject to change or discontinuation at any time.

5. At-Will Employment . Your employment with the Company is and shall at all times during your employment hereunder be “at-will” employment. The Company or you may terminate your employment at any time for any reason, with or without cause, and with or without notice. The “at-will” nature of your employment shall remain unchanged during your tenure as an employee of the Company, and may only be changed by an express written agreement that is signed by you and the Company.

6. Employee Confidentiality Agreement . As an employee of the Company, you will have access to certain Company and third party confidential information and you may during the course of your employment develop certain information or inventions which will be the property of the Company. You acknowledge the continuing effectiveness of the Nondisclosure and Inventions Assignment Agreement between you and the Company, dated August 18, 2014.

7. Resolution of Disputes . Any controversy or claim arising out of or relating to your employment, this letter agreement, its enforcement or interpretation, or because of an alleged breach, default, or misrepresentation in connection with any of its provisions, shall be submitted to arbitration in Boston, Massachusetts before a single arbitrator (applying Massachusetts law), in accordance with the National Rules for the Resolution of Employment Disputes then in effect of the American Arbitration Association ( “AAA” ) as modified by the terms and conditions of this Section 7; provided , however, that provisional injunctive relief may,

but need not, be sought in a court of law while arbitration proceedings are pending, and any provisional injunctive relief granted by such court shall remain effective until the matter is finally determined by the arbitrator. The arbitrator shall be selected by mutual agreement of the parties or, if the parties cannot agree, by striking from a list of arbitrators supplied by AAA. The arbitrator shall issue a written opinion revealing, however briefly, the essential findings and conclusions upon which any award is based. Final resolution of any dispute through arbitration may include any remedy or relief which the arbitrator deems just and equitable. Any award or relief granted by the arbitrator hereunder shall be final and binding on the parties hereto and may be enforced by any court of competent jurisdiction.

The parties acknowledge that they are hereby waiving any rights to trial by jury in any action, proceeding or counterclaim brought by either of the parties against the other in connection with any matter whatsoever arising out of or in any way connected with this letter agreement or your employment.

The arbitrator shall have the sole and exclusive power and authority to decide any and all issues of or related to whether this letter agreement or any provision of this letter agreement is subject to arbitration.

8. No Inconsistent Obligations . By accepting this offer of employment, you represent and warrant to the Company that you are under no obligations or commitments, whether contractual or otherwise, that are inconsistent with your obligations set forth in this letter agreement or that would be violated by your employment by the Company. You agree that you will not take any action on behalf of the Company or cause the Company to take any action that will violate any agreement that you have with a prior employer.

9. Miscellaneous .

a. This letter agreement may be executed in several counterparts, each of which shall be deemed to be an original but all of which together will constitute one and the same instrument.

b. The Company may only assign this letter agreement to a successor (whether direct or indirect by purchase, merger, consolidation or otherwise) to all or substantially all of the business and/or assets of the Company, provided, that such successor expressly agrees to assume and perform this letter agreement in the same manner and to the same extent that the Company would have been required to perform it if no such assignment had taken place, and “Company” shall include any such successor that assumes and agrees to perform this letter agreement, by operation of law or otherwise.

c. No provision of this letter agreement may be modified, waived or discharged unless such waiver, modification or discharge is agreed to in writing and signed by you and the Company. No waiver by either party hereto at any time of any breach by the other party hereto of, or compliance with, any condition or provision of this letter agreement to be performed by such other party shall be deemed a waiver of similar or dissimilar provisions or conditions at the same or at any prior or subsequent time.

10. Section 409A . It is intended that this letter agreement comply with or be exempt from Section 409A of the Internal Revenue Code of 1986, and the Treasury Regulations and IRS guidance thereunder (collectively referred to as “Section 409A”), and notwithstanding anything to the contrary herein, it shall be administered, interpreted, and construed in a manner consistent with Section 409A. To the extent that any reimbursement, fringe benefit, or other, similar plan or arrangement in which you participate provides for a “deferral of compensation” within the meaning of Section 409A, (a) the amount of expenses eligible for reimbursement provided to you during any calendar year shall not affect the amount of expenses eligible for

reimbursement or in-kind benefits provided to you in any other calendar year, (b) the reimbursements for expenses for which you are entitled to be reimbursed shall be made on or before the last day of the calendar year following the calendar year in which the applicable expense is incurred, (c) the right to payment or reimbursement or in-kind benefits hereunder may not be liquidated or exchanged for any other benefit, and (d) the reimbursements shall be made pursuant to objectively determinable and nondiscretionary Company policies and procedures regarding such reimbursement of expenses. If and to the extent required to comply with Section 409A, no payment or benefit required to be paid under this letter agreement on account of termination of your employment shall be made unless and until you incur a “separation from service” within the meaning of Section 409A. In the case of any amounts payable to you under this letter agreement that may be treated as payable in the form of “a series of installment payments”, as defined in Treasury Regulation Section 1.409A-2(b)(2)(iii), your right to receive such payments shall be treated as a right to receive a series of separate payments for purposes of such Treasury Regulation. If any paragraph of this letter agreement provides for payment within a time period, the determination of when such payment shall be made within such time period shall be solely in the discretion of the Company.

11 . The validity, interpretation, construction and performance of this letter agreement shall be governed by the laws of the Commonwealth of Massachusetts without regard to the choice of law principles thereof.

[Signatures appear on following page]